Differential Expression of Nephrin According to Glomerular Size in Early Diabetic Kidney Disease

Abstract

Diabetic nephropathy (DN) is clinically characterized by proteinuria. Many studies tried to demonstrate a relationship between proteinuria and changes in nephrin in various forms of glomerular diseases including DN, but the results are not consistent. Glomerular hypertrophy occurs in DN, yet hypertrophy does not develop in all glomeruli concurrently. For investigation of the differences in nephrin expression according to glomerular size, glomeruli were isolated from 10 control and 10 streptozotocin-induced diabetic rats at 6 wk after the induction of diabetes by a sieving technique using sieves with pore sizes of 250, 150, 125, and 75 m. Glomeruli then were classified into large glomeruli (LG; on the 125-m sieve) and small glomeruli (SG; on the 75-m sieve) groups. Glomerular volumes were determined using an image analyzer, and mRNA and protein expression was determined by real-time PCR and Western blot, respectively. The mean volumes of diabetic LG (1.51 Ϯ 0.06 ϫ 10 6 m 3 ) and control LG (1.37 Ϯ 0.05 ϫ 10 6 m 3 ) were significantly higher than those of diabetic SG (0.94 Ϯ 0.03 ϫ 10 6 m 3 ) and control SG (0.87 Ϯ 0.03 ϫ 10 6 m 3 ; P Ͻ 0.01). Nephrin mRNA expression was significantly reduced in the diabetic LG group compared with the diabetic SG and control glomeruli groups (P Ͻ 0.05). In contrast, nephrin mRNA expression was significantly higher in the diabetic SG group compared with the diabetic LG and control glomeruli groups (P Ͻ 0.05). Even after correction for 18s rRNA and Wilms' tumor-1 mRNA expression, the differences in nephrin mRNA expression remained significant. The expression of nephrin protein showed a similar pattern to the mRNA expression. In conclusion, these data suggest that the nephrin gene is differentially expressed according to glomerular size. Furthermore, more hypertrophied glomeruli with lesser nephrin expression may be responsible for albuminuria in the early stage of DN.

Inducible Overexpression of sFlt-1 in Podocytes Ameliorates Glomerulopathy in Diabetic Mice

“…In experimental animal models of diabetes, nephrin expression has been reported to be either upregulated or downregulated (10,(37)(38)(39). In our diabetic mice, nephrin was upregulated when compared with control nondiabetic animals, and the podocyte overexpression of sFlt-1 did not affect this upregulation.…”

Increased SHP-1 Protein Expression by High Glucose Levels Reduces Nephrin Phosphorylation in Podocytes

“…The loss of podocytes is thought to be a key event in DN. It has been reported previously that mice and humans with diabetes exhibit a disruption of nephrin expression (27,28). Furthermore, a previous study showed that podocytes expressing a mutated form of nephrin displayed increased apoptosis in response to serum starvation (29), suggesting a relationship with the absence of nephrin signaling actions.…”

Pathological influence of obesity on renal structural changes in chronic kidney disease

“…Glomerulomegaly is also observed in the kidneys of diabetic nephropathy and hypertensive kidney [1,6,8]. An increase in glomerular volume is usually the consequence of glomerular hyperfiltration, and can be associated with expansion of capillary loops [8,9,10].…”

“…An increase in glomerular volume is usually the consequence of glomerular hyperfiltration, and can be associated with expansion of capillary loops [8,9,10]. Obesity can accelerate renal dysfunction in patients with glomerulonephritis such as IgA nephropathy (IgAN).…”